Hyperhomocysteinemia in end-stage renal disease: Prevalence, etiology, and potential relationship to arteriosclerotic outcomes

Abstract

The end-stage renal disease (ESRD) population requiring chronic maintenance dialysis or renal transplantation is growing at an exponential rate, with over 62,000 incident (newly developed ESRD) cases reported per year in the United States [1]. This patient population experiences an excess morbidity and mortality due to arteriosclerotic cardiovascular disease (CVD) outcomes [1—5]. Specifically, event rates for myocardial infarction and stroke are 5to 10-fold higher in ESRD versus general populations [1—5]. Traditional CVD risk factors, such as smoking, hypertension, glucose intolerance/diabetes, and dyslipidemia [6], despite their widespread prevalence [7], are relatively limited predictors of CVD-specific morbidity and mortality in the ESRD population [7—111. Wu [10], for example, reported that the two-year cumulative incidence of de novo coronary heart disease (CHD) in ESRD patients undergoing chronic peritoneal (18.0%) or hemodialysis (15.0%), exceeded the six-year cumulative incidence (12.7%) of de novo CHD among original Framingham Study cohort participants similarly free of baseline CHD, and frequency matched to the dialysis patients for prevalence of the established CVD risk factors. Recently, controlled evidence [12] has been provided that hyperhomocysteinemia, that is, elevated total plasma levels of the atherothrombotic sulfur amino acid homocysteine [13, 14], occurs more commonly than any of the traditional CVD risk factors in ESRD patients on maintenance dialysis. Initial follow-up data further suggest that the markedly elevated fasting plasma total homocysteine (tHcy) levels found in these dialysis-dependent ESRD patients contributes independently to their excess incidence of fatal and non-fatal CVD outcomes [15]. Confirmation of these prospective findings in more sizable ESRD cohorts is urgently required. This review will first place hyperhomocysteinemia in the context of the other established amino acid abnormalities characteristic of ESRD. What is known from studies of general and ESRD populations about the prevalence and pathogenesis of hyperhomocysteinemia will then be summarized, followed by discussions of the epidcmiological and experimental evidence linking hyper-